Dataset Information

The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.

ABSTRACT: Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them-and perhaps also the other dipeptides-as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity.

SUBMITTER: Altmaier E

PROVIDER: S-EPMC4847917 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.

Altmaier Elisabeth E Menni Cristina C Heier Margit M Meisinger Christa C Thorand Barbara B Quell Jan J Kobl Michael M Römisch-Margl Werner W Valdes Ana M AM Mangino Massimo M Waldenberger Melanie M Strauch Konstantin K Illig Thomas T Adamski Jerzy J Spector Tim T Gieger Christian C Suhre Karsten K Kastenmüller Gabi G

PloS one 20160427 4

Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associate ...[more]

PMID: 27120469

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Project description:BackgroundThe application of metabolomics-based profiles in environmental epidemiological studies is a promising approach to refine the process of health risk assessment. We aimed to identify potential metabolomics-based profiles in urine and plasma for the detection of relatively low-level cadmium (Cd) exposure in large population-based studies.MethodWe analyzed 123 urinary metabolites and 94 plasma metabolites detected in fasting urine and plasma samples collected from 1,412 men and 2,022 women involved in the Tsuruoka Metabolomics Cohort Study. Regression analysis was performed for urinary N-acetyl-beta-D-glucosaminidase (NAG), plasma, and urinary metabolites as dependent variables, and urinary Cd (U-Cd, quartile) as an independent variable. The multivariable regression model included age, gender, systolic blood pressure, smoking, rice intake, BMI, glycated hemoglobin, low-density lipoprotein cholesterol, alcohol consumption, physical activity, educational history, dietary energy intake, urinary Na/K ratio, and uric acid. Pathway-network analysis was carried out to visualize the metabolite networks linked to Cd exposure.ResultUrinary NAG was positively associated with U-Cd, but not at lower concentrations (Q2). Among urinary metabolites in the total population, 45 metabolites showed associations with U-Cd in the unadjusted and adjusted models after adjusting for the multiplicity of comparison with FDR. There were 12 urinary metabolites which showed consistent associations between Cd exposure from Q2 to Q4. Among plasma metabolites, six cations and one anion were positively associated with U-Cd, whereas alanine, creatinine, and isoleucine were negatively associated with U-Cd. Our results were robust by statistical adjustment of various confounders. Pathway-network analysis revealed metabolites and upstream regulator changes associated with mitochondria (ACACB, UCP2, and metabolites related to the TCA cycle).ConclusionThese results suggested that U-Cd was associated with metabolites related to upstream mitochondrial dysfunction in a dose-dependent manner. Our data will help develop environmental Cd exposure profiles for human populations.

Project description:BackgroundThe role of diet in health is well established and, in the past decade, more attention has been given to the role of food choices in the environment. The agricultural sector produces about a quarter of the world's greenhouse gas emissions (GHGE), and meat production, especially beef, is an important contributor to global GHGE. Our study aimed to address a fundamental gap in the diet-climate literature: identifying consumers who are receptive to making dietary changes, and the effect of their potential changes on GHGE, diet healthfulness, and diet costs.MethodsDietary data on US individuals from a nationally representative survey were linked to food-related GHGE. We identified individuals receptive to changing their diets (potential changers) as those who reported trying US dietary guidance and were likely to agree that humans contribute to climate change. We assessed GHGE, diet healthfulness measured by the Healthy Eating Index (HEI), and diet costs before and after hypothetical changes replacing either beef or meats with poultry or plant-protein foods.FindingsOur sample comprised 7188 individuals, of whom 16% were potential changers. These were disproportionately women, highly educated, or had higher income compared with individuals deemed not likely to change. Replacing 100% of beef intake in potential changers with poultry reduced mean dietary GHGE by 1·38 kg CO2-equivalents per person per day (95% CI 1·19-1·58), a 35·7% decrease. This replacement also increased mean HEI by 1·7% and reduced mean diet costs by 1·7%. We observed the largest changes when replacing all beef, pork, or poultry intake with plant-protein foods (GHGE decreased by 49·6%, mean HEI increased by 8·7%, and dietary costs decreased by 10·5%). Hypothetical replacements in the potential changers alone resulted in whole population reductions in 1-day dietary GHGE of 1·2% to 6·7%, equivalent to 22-126 million fewer passenger vehicle km.InterpretationIndividual-level diet studies that include a variation in response by consumers can improve our understanding of the effects of climate policies such as those that include sustainability information in national dietary guidance. In our study, we found that changes by a small percentage of motivated individuals can modestly reduce the national dietary GHGE. Moreover, these substitutions can modestly improve diet healthfulness and reduce diet costs for individuals who make these changes.FundingWellcome Trust.

Project description:PurposeRadiation-induced lung injury is a major dose-limiting toxicity for thoracic radiation therapy patients. In experimental models, treatment with angiotensin converting enzyme (ACE) inhibitors mitigates radiation pneumonitis; however, the mechanism of action is not well understood. Here, we evaluate the direct role of ACE inhibition on lung immune cells.Methods and materialsACE expression and activity were determined in the lung immune cell compartment of irradiated adult rats after either high dose fractionated radiation therapy to the right lung (5 fractions × 9 Gy) or a single dose of 13.5 Gy partial body irradiation. Mitigation of radiation-induced pneumonitis with the ACE-inhibitor lisinopril was evaluated in the 13.5 Gy rat partial body irradiation model. During pneumonitis, we characterized inflammation and immune cell content in the lungs and bronchoalveolar lavage fluid. In vitro mechanistic studies were performed using primary human monocytes and the human monocytic THP-1 cell line.ResultsIn both the partial body irradiation and fractionated radiation therapy models, radiation increased ACE activity in lung immune cells. Treatment with lisinopril improved survival during radiation pneumonitis (P = .0004). Lisinopril abrogated radiation-induced increases in bronchoalveolar lavage fluid monocyte chemoattractant protein 1 (chemokine ligand 2) and MIP-1a cytokine levels (P < .0001). Treatment with lisinopril reduced both ACE expression (P = .006) and frequency of CD45+ CD11b+ lung myeloid cells (P = .004). In vitro, radiation injury acutely increased ACE activity (P = .045) and reactive oxygen species (ROS) generation (P = .004) in human monocytes, whereas treatment with lisinopril blocked radiation-induced increases in both ACE and ROS. Radiation-induced ROS generation was blocked by pharmacologic inhibition of either NADPH oxidase 2 (P = .012) or the type 1 angiotensin receptor (P = .013).ConclusionsThese data demonstrate radiation-induced ACE activation within the immune compartment promotes the pathogenesis of radiation pneumonitis, while ACE inhibition suppresses activation of proinflammatory immune cell subsets. Mechanistically, our in vitro data demonstrate radiation directly activates the ACE/type 1 angiotensin receptor pathway in immune cells and promotes generation of ROS via NADPH oxidase 2.

Dataset Information

The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.

Publications

The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.

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